Method of treating actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate)

ABSTRACT

The invention relates to the topical treatment of actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate).

FIELD OF THE INVENTION

The invention relates to the topical treatment of actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate).

CROSS-REFERENCE RELATED APPLICATIONS

This application for U.S. patent claims priority to EP patent application No. 13190223.1, filed 25 Oct. 2013, the contents of which is incorporated herein by reference in its entirety, EP patent application No. 14161730.8, filed 26 Mar. 2014, the contents of which is incorporated herein by reference in its entirety, and EP patent application No. 14165659.5, filed 23 Apr. 2014, the contents of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The active compound, ingenol 3-(3,5-diethylisoxazole-4-carboxylate), of the present invention has previously been described in PCT/DK2011/000154. The compound has previously been studied with respect to safety and tolerability for field therapy in 25 cm² on 4 separate areas on the forearm in concentrations of 0.025%, 0.05% and 0.075% in a gel formulation.

Existing topical treatments for actinic keratosis on the balding scalp comprises different dosage regimens. All of them extend over weeks and/or months. Picato® which is launched in many countries around the world for treatment of actinic keratosis on the face or balding scalp has a dosage regimen of two or three days depending on the location of the actinic keratosis. According to the FDA label for Picato®, the size of the treatment area is limited to about 25 cm² (2 inches×2 inches).

SUMMARY OF THE INVENTION

The present invention provides a topical treatment regimen for actinic keratosis (AK) which is of short duration and applicable to a large skin area, a full balding scalp. The treatment is simple by the two day regimen. The treatment is directed against treating nonhyperkeratotic actinic keratosis. The treatment is optimized towards acceptable side-effects in terms of measured local skin reactions (LSR).

The invention provides a method of treating a subject diagnosed with actinic keratosis on the balding scalp, said method comprising applying topically an effective amount of the active compound, ingenol 3-(3,5-diethylisoxazole-4-carboxylate), to a treatment area for two days to achieve reduction in the number of the actinic keratosis in the treated area.

DETAILED DESCRIPTION OF THE INVENTION

From Picato® and other topical agents used in the treatment of actinic keratosis, it is well known that differences in treatment efficacy exists between different anatomical regions. Regions like scalp, trunk (except chest) and extremities are more difficult to treat than the face. From the Picato® studies, it has been shown that local skin reactions after a given dose are milder on difficult to treat anatomical regions than on anatomical regions more easily treated with the compound. For these reasons the present invention has discovered a novel treatment of the balding scalp only.

The present invention simplifies prior and existing treatments by a simple two day regimen independent of the location of the actinic keratosis.

The present invention describes treatment of actinic keratosis on the full balding scalp.

The lesions are not of atypical clinical appearance such as for example hypertrophic, hyperkeratotic or cutaneous horns and/or recalcitrant diseases, such as non-responding to cryotherapy on two previous occasions.

Quite remarkably, local skin reactions (LSRs) occurs only sometimes in the treated area. Often LSRs are quantified by a scale evaluating the following types of skin reactions: erythema, flaking/scaling, crusting, swelling, vasiculation/postulation, and erosion/ulceration which are categorized into categories 0-4 depending on the severity of the reactions.

In the trial pre-defined grades of LSRs will constitute Dose Limiting Toxicity (DLT). The level of skin reactivity constituting DLT does not reflect safety concerns but represent what dermatologists consider limits for peak levels of acceptable visible skin reactions.

Dose Limiting toxicity (DLT) is defined as:

-   -   Erosion/ulceration Grade 4 on the LSR scale     -   other clinically relevant signs or symptoms observed, which the         Investigator judges to be counted as a DLT

Maximum tolerated dose (MTD) is declared as the highest dose level at which less than 4 subjects out of 12 experience a DLT.

The study is designed in two parts:

Part 1 is a dose escalation study conducted with a once daily application of trial medication for two consecutive days and continue until the MTD has been identified. Dose escalation will only proceed if the safety and tolerability data of the subject up to day 8 is reviewed and considered satisfactory. The treatment consists of once daily treatment for 2 consecutive days. The starting dose is 0.025% and the doses are administered in an escalating manner following review of safety and tolerability. Up to 5 different doses may be investigated in cohorts of 1 subject. The number of subjects in each cohort will depend on the number of observed DLTs. However, the MTD will always be confirmed in a cohort of 12 subjects.

Part 2 is a study of the efficacy of the MTD level identified in part 1 and the level below the identified level. Lower levels can however be chosen instead for Part 2.

The outcome for Part 2 is efficacy in clearance of the AK.

The trial medication applied is preferably a gel. The gel formulation comprises; isopropyl alcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water and active compound in various suitable concentrations.

The active compound is ingenol 3-(3,5-diethylisoxazole-4-carboxylate).

The present invention relates to the treatment of actinic keratosis lesions on full balding scalp by a once daily, two day treatment. More specifically, the invention relates to the treatment of actinic keratosis lesions in an area of approximately 250 cm² on the full balding scalp in a two day treatment. In case the balding scalp contains hairy areas, which reduces the treated area, the amount of compound applied should be reduced proportionately if feasible.

In accordance with any of the above embodiments, the two day treatment is two consecutive days.

In one embodiment, the present invention provides the method according to the above, wherein the effective amount of active compound is applied in a gel or other topical formulation from a dosage strength formulation of active compound of between about 0.01% and about 0.1%

In another embodiment, the present invention provides the active compound formulated in an effective amount in a gel formulation comprising ispropylalcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water.

In another embodiment, the present invention provides application of active compound in a concentration of about 0.018%, about 0.025%, about 0.037%, about 0.050%, about 0.075% or about 0.1%.

In yet another embodiment, the present invention provides topical application of the active compound in a concentration of between about 0.037% and about 0.05%, and more preferably about 0.037% and about 0.05%.

In still a further embodiment, the present invention provides the amount of active compound applied is between about 0.162 mg active compound/per day/250 cm² treated area to about 0.9 mg active compound/per day/250 cm² treated area, and more preferably about 0.162 mg active compound/per day/250 cm2 treated area and about 0.9 mg active compound/per day/250 cm2 treated area.

In another embodiment, the present invention provides a method of treating a subject diagnosed with actinic keratosis, said method comprising applying topically an effective amount of active compound to a treatment area for two days to achieve a reduction in the number of actinic keratosis lesions in the treated area.

EXAMPLE

Subjects who qualify for Part 1 of the trial must have 5 to 20 clinically typical, visible and discrete actinic keratosis on the balding scalp. The balding scalp must be between 125 cm² and 250 cm².

To be included in the trial, Part 2, the subjects must have 5-20 clinically typical, visible and discrete actinic keratosis on the balding scalp. The balding scalp must be of a size of between 25 cm² and 250 cm².

Part 1: Trial medication will be applied to full balding scalp once daily for two consecutive days until the maximum tolerated dose has been reached for each formulation. Up to nine different doses of active compound in gel or a cream may be investigated in cohorts of 3 to 12 subjects. Pre-defined grades of Local Skin Responses (LSRs) will constitute dose limiting toxicity (DLT). The maximum tolerated dose is defined as the highest dose level at which less than 4 out of 12 subjects experience a Dose limiting toxicity.

The doses will be administered in an escalating manner following review of safety and tolerability data performed by the dose escalation committee. Evaluation of the safety and tolerability data will be performed after Visit 5/day 8. Then subjects will be followed for 8 weeks after first application of investigational product.

Part 2 of the trial may include a total of 124 subjects: 62 subjects in each of the 2 active treatment arms (Part 1 identified dose and the dose below) and additionally 31 subjects in a vehicle arm.

To be included in the trial, Part 1, the subjects must be at least 18 years of age. Exclusion criteria is incompletely healed wound, basal cell carcinoma or squamous cell carcinoma within a 5 cm of treatment area, or prior treatment with Picato® (ingenol mebutate) gel on the treatment area, or atypical clinical appearance on the lesions such as hypertrophic, hyperkeratotic or cutaneous hors, and/or recalcitrant disease such as non-responding to cryotherapy on two previous occasions. Also other skin conditions, cosmetic procedures or other disease or medication which could interfere with the evaluation of the trial medication or the assessments of the treated area are exclusion criteria, as is other disease or medical conditions which make the subject unsuitable to participate in the trial.

The patients are scheduled for 6 visits:

Visit 1: within 35 days prior to day 1

Visit 2: day 1 (application of trial medication)

Visit 3: day 2 (application of trial medication)

Visit 4: day 3

Visit 5: day 8 (±1 day)

Visit 6: week 2

LSRs are evaluated at all visits following visit 1.

An Evaluable Subjects analysis set will be defined as all subjects who receive at least one dose, and have LSRs recorded at all visits up to and including day 8 or have experienced a DLT at one or more visits up to and including day 8. Safety analyses will be based on the safety analysis set, which is defined as all subjects who receive at least one application of trial medication and have safety information available post treatment.

In part 2 the patients are scheduled for 7 visits:

Visit 1: within 21 days prior to day 1

Visit 2: day 1 (application of trial medication)

Visit 3: day 2 (application of trial medication)

Visit 4: day 3

Visit 5: day 8 (±1 day)

Visit 6: week 2

Visit 7: week 8

LSRs are evaluated at all visits following visit 1. AK lesion counts are performed on visit 6 and 7.

Efficacy analyses will be based on the full analysis set, which will be defined as all randomized subjects. Per protocol analysis set will be used as an efficacy subset and will be defined as subjects in the full analysis set who complete the study without major protocol deviations. Safety analyses will be based on the safety analysis set, which is defined as all subjects who receive at least one application of trial medication and have safety information available post treatment.

At visit 7 in week 8, the ratio of number of lesions at week 8 relative to baseline will be tabulated by treatment group and analyzed using a negative binomial regression on actinic keratosis count at week 8 with the log baseline value as an offset variable and treatment group and analysis site as factor. The rate ratios and the corresponding 95% confident intervals will be estimated from this model comparing the active groups pairwise.

Complete clearance of AKs at week 8 will be analyzed by log binomial regression with factors: Treatment group and analysis site. The number of baseline lesions will be included as a continuous variable. The rate ratios of pairwise treatment groups will be presented together with their 95% confidence intervals. Partial clearance, defined as 75% or greater reduction in AK count will be analyzed in the same way as complete clearance.

The incidence and grade of LSRs will be summarized by treatment arm overall at each visit. Local skin response grades will be summarized by frequency counts and descriptive statistics by treatment arm for each of the six individual LSRs: erythema, flaking/scaling, crusting, swelling, vesiculation/postulation, and erosion/ulceration.

A composite score will be obtained by summing the six individual LSR scores at each visit. The composite score and change from baseline will be summarized by treatment arm at each visit using descriptive statistics.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. 

What is claimed is:
 1. A method of treating a subject diagnosed with actinic keratosis on the full balding scalp, said method comprising topically applying an effective amount of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) to a treatment area on the full balding scalp for two days.
 2. The method of claim 1, wherein the method provides reduction in the number of actinic keratosis lesions in the treated area on the full balding scalp.
 3. The method of claim 1, wherein the two days treatment is two consecutive days.
 4. The method of claims 1-3, wherein the treated area is of a size up to about 250 cm².
 5. The method of any of the claim 1, wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of between about 0.01% and about 0.1%.
 6. The method of any of the claim 2, wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of between about 0.01% and about 0.1%
 7. The method of any of the claim 3, wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of between about 0.01% and about 0.1%.
 8. The method of any of the claim 4, wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) of between about 0.01% and about 0.1%.
 9. The method of claim 1, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
 10. The method of claim 2, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
 11. The method of claim 3, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
 12. The method of claim 4, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
 13. The method of claim 1, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.037% and about 0.05%.
 14. The method of claim 1, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.037%.
 15. The method of claim 1, wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.05%.
 16. The method of any of the claim 1, wherein the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is formulated in a gel.
 17. A method of treating a subject diagnosed with actinic keratosis on the full balding scalp, said method comprising topically applying an effective amount of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) to a treatment are on the full balding scalp for two consecutive days, wherein said method provides a reduction in the number of actinic keratosis lesions in the treated area on the full balding scalp, wherein the treated area is of a size up to about 250 cm², and wherein the dosage strength of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.037% and about 0.05%. 